Stereotactic body radiation extends survival in hepatocellular carcinoma
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Stereotactic body radiation therapy followed by sorafenib extended survival compared with sorafenib alone among patients with hepatocellular carcinoma, according to study results presented at ASCO Gastrointestinal Cancers Symposium.
Patients treated with stereotactic body radiation therapy (SBRT) achieved longer PFS and OS with no increase in adverse events, results of the NRG Oncology/RTOG 1112 study showed.
Researchers also reported “a strong suggestion” of quality-of-life benefit at 6 months in the SBRT group.
“The take-home message is that radiation is an effective therapy for patients with advanced hepatocellular carcinoma,” Laura A. Dawson, MD, FRCPC, FASTRO, chair of the department of radiation oncology at University of Toronto and practicing radiation oncologist at Princess Margaret Cancer Centre, told Healio. “I hope oncologists and radiation oncologists keep this in mind for patients, particularly those who have macrovascular invasion — and especially if they are treated with a tyrosine kinase inhibitor.”
HCC is among the leading causes of cancer death worldwide, and incidence is increasing in North America.
Systemic care is standard for patients with HCC ineligible for surgical resection or invasive therapies.
Prior research suggested a benefit of integrating radiation therapy into HCC management; however, most studies have been single arm, and the findings did not change practice due to lack of comparator.
“There are very few randomized studies that have accrued with substantial number of patients that have the power to show benefit, so that was the rationale for this study,” Dawson said.
The NRG Oncology/RTOG 1112 trial assessed whether SBRT followed by sorafenib (Nexavar, Bayer) could improve outcomes.
Researchers enrolled 193 patients with new or recurrent HCC unsuitable for surgery, ablation or transarterial chemoembolization.
The analysis included 177 eligible patients (median age, 66 years; range, 27-84), all of whom had Zubrod performance status of 0 to 2, Child-Pugh class A disease and Barcelona Clinic Liver Cancer stage B (18%) or C (82%) disease, with distant metastases no larger than 3 cm.
The majority (74%) had macrovascular invasion, with 63% having VP3 or VP4 macrovascular invasion; 41% had hepatitis C virus and 19% had either hepatitis B virus or hepatitis B/C virus; 4% had metastases and 40% had a single HCC. Median sum of max diameter of HCCs was 8.2 cm in the sorafenib group and 6.7 cm in the SBRT/sorafenib group.
Researchers randomly assigned 92 patients to 400 mg sorafenib twice daily. The other 85 patients received SBRT (27.5 Gy to 50 Gy in five fractions) followed by 200 mg sorafenib twice daily, increasing to 400 mg twice daily after 28 days.
About one in five (22%) of those assigned sorafenib received SBRT after sorafenib discontinuation.
OS served as the primary endpoint. Secondary endpoints included PFS, adverse events and quality of life, measured by improvement of at least five points in FACT-Hep score from baseline to 6 months.
Median follow-up was 13.2 months for all patients and 33.7 months for those who remained alive at data cutoff.
Unadjusted OS analysis showed a numerical improvement in the SBRT/sorafenib group (15.8 months vs. 12.3 months; HR = 0.77). Analysis adjusted for performance status, degree of macrovascular invasion and other factors showed a statistically significant improvement in the SBRT/sorafenib group (HR = 0.72; 95% CI, 0.52-0.99).
Researchers also reported longer median PFS in the SBRT/sorafenib group (9.2 months vs. 5.5 months; HR = 0.55; 95% CI, 0.4-0.75).
“From my experience, I’m aware that patients with hepatocellular carcinoma can respond very well to radiotherapy. Even though I was very pleased with the results, I was not overwhelmingly surprised,” Dawson said. “I think these benefits are clinically important and very meaningful to patients.”
A comparable percentage of patients in the sorafenib and SBRT/sorafenib groups experienced grade 3 or higher adverse events (42% vs. 47%). These included nausea, increased bowel movement frequency, transient liver enzyme elevation and platelet decrease, Dawson said.
Researchers reported grade 5 adverse events among two patients assigned sorafenib alone (one case of hepatic failure and one death not otherwise specified) and one assigned SBRT/sorafenib (lung infection). Grade 3 or higher bleeds occurred among five patients assigned sorafenib (variceal, n = 1; upper GI, n = 2; hepatic, n = 1; abdominal, n = 1) and three assigned SBRT/sorafenib (upper GI, n = 2; lower GI, n = 1).
“If anything, grade 4 or grade 5 events tended to be less frequent [in the SBRT group], probably because the majority of serious adverse events are due to the underlying cancer rather than treatment itself,” Dawson said. “If therapy can improve the control of the cancer that is in the vein and likely to cause sequalae of liver failure or bleeding, there will be less of those events. Even though there’s more treatment, there are fewer serious adverse events because tumors are being controlled better for longer.”
Among 37 patients (sorafenib, n = 20; SBRT/sorafenib, n = 17) with quality-of-life assessments at baseline and 6 months, a higher percentage of those assigned SBRT/sorafenib achieved improvement in FACT-Hep scores (35% vs. 10%).
“It becomes a little bit tricky to address how radiation fits in the immunotherapy era, and there are a variety of opinions,” Dawson told Healio. “There probably will be randomized studies with immunotherapy and radiation. Even if they are not plus-or-minus-radiotherapy studies, I hope radiation is considered in future trial design and guidelines, because it is a very effective therapy.”
Perspective
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Karyn A. Goodman, MD, MS
RTOG 1112 is a large prospective, randomized phase 3 trial designed to evaluate the benefit of the addition of SBRT to the standard of care at the time — sorafenib — for patients with advanced, unresectable HCC who were not candidates for ablation or transarterial chemoembolization. This is a landmark study, as it was the first to evaluate the use of SBRT for HCC in a randomized trial. Despite early closure due to slow accrual after the standard management of HCC shifted away from the use of sorafenib, RTOG 1112 demonstrated OS and PFS benefits with the addition of SBRT to systemic therapy. The study is groundbreaking in that it demonstrated a survival benefit and improved quality of life indicators with the use of local therapy with SBRT in the setting of advanced HCC. Moreover, SBRT was well-tolerated and didn’t increase risk for adverse events in this high-risk and potentially sick population. Although sorafenib has been replaced by immunotherapy-based regimens for the management of advanced HCC, RTOG 1112 has established the use of SBRT for patients who may not be candidates for immunotherapy and are receiving sorafenib or other tyrosine kinase inhibitors. Additional studies evaluating the role of SBRT in the setting of the new standard approach using immunotherapy are planned, where there may be a greater impact of combining the antigen-presenting effect of SBRT with immune checkpoint inhibition.
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Dawson LA, et al. Abstract 489. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
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